The present invention relates to pharmaceutical compositions comprising TGF-β superfamily members. Particularly, the invention provides improved pharmaceutical compositions comprising TGF-β superfamily members, wherein the compositions provide improved recovery of the TGF-β superfamily members and/or improved biological activity of the TGF-β superfamily members incorporated in the compositions. The invention also provides methods utilising such pharmaceutical compositions. Furthermore, the invention also provides medicaments for the prevention or reduction of injection pain.
The Transforming Growth Factor-Betas (TGF-βs) represent a family of cytokines having diverse biological activities. The TGF-βs belong to a wider group of related cytokines known as the TGF-β superfamily. Members of the TGF-β superfamily include activins, bone morphogenetic proteins (BMPs), anti-Müllerian hormone (AMH), the glial cell line derived neurotrophic factor (GDNF) subfamily and the growth/differentiation factor (GDF) subfamily. TGF-β superfamily members share structural similarities, such as a common cysteine knot motif, as well as common signal transduction pathways. Illustrative examples of members of the TGF-superfamily are shown in FIG. 1.
The biological activities of members of the TGF-β superfamily have utility in many different therapeutic contexts, and accordingly there is much interest in the pharmaceutical application of TGF-β superfamily members.
TGF-β1, TGF-β2 and TGF-β3 are known to play crucial roles in the regulation of the wound healing response, while osteoinduction modulated by BMPs is useful in the therapeutic application of bone formation, healing and remodelling.
TGF-β1 has uses in the prevention and/or treatment of scleroderma, angiogenesis disorders, renal disease, osteoporosis, bone disease, glomerulonephritis and renal disease.
TGF-β2 may be used in the treatment of glioma, non-small-cell lung cancer, pancreas tumour, solid tumours, colon tumour, ovary tumour, age-related macular degeneration, ocular injury, osteoporosis, retinopathy, ulcers, carcinoma, mouth inflammation and scleroderma.
TGF-β3 may be used in the treatment of fibrotic disorders, scleroderma, angiogenesis disorders, restenosis, adhesions, endometriosis, ischemic disease, bone and cartilage induction in vitro fertilisation, oral mucositis, renal disease, prevention, reduction or inhibition of scarring, enhancement of neuronal reconnection in the peripheral and central nervous system, preventing, reducing or inhibiting complications of eye surgery (such as LASIK or PRK surgery).
Many other members of the TGF-β superfamily are also known to have therapeutic applications. For example, glial cell line derived neurotrophic factor (GDNF) has been suggested to be useful in the treatment of many neurodegenerative and neurological diseases (such as Parkinson's disease, motor neurone disease, Alzheimer's disease, and Huntington's chorea) as well as in wound healing, treatment of scar tissue and ocular applications in treatment of corneal tissue and corneal disease.
Artemin (which is also known as neublastin or enovin) is suitable for use in the prevention and/or treatment of neurodegenerative disease, neuropathic pain and neuropathy.
Neurturin has therapeutic applications in Parkinson's disease and other neurological diseases.
Persephin is believed to have therapeutic utility in the treatment of such conditions as inflammation, multiple sclerosis, neoplasm, healing of wounds and other injuries, Acquired immune deficiency syndrome (AIDS), bacterial, viral and other infections, immune deficiency, Alzheimer's disease, Huntington's chorea, Parkinson's disease, cerebrovascular ischemia, and degenerative diseases.
BMP 15 (also known as Growth Differentiation Factor 9B) is useful in the treatment of female infertility, in contraception, as well as in cases of bone injury and wound healing.
The superfamily member GDF9 has therapeutic utility in the treatment of female infertility.
Nodal may be used in the treatment of muscle disease, osteoporosis, osteoarthritis, wound healing, periodontal disease and connective tissue disease.
BMP3 has medical uses in the fields of bone injury, osteoporosis, wound healing, nervous system injury, neurodegenerative disease, Parkinson's disease, cerebrovascular disease and renal disease. BMP3b may be used in the treatment of birth complications.
BMP-5 may be used to treat many of the same indications as BMP-3, as well as osteoporosis, connective tissue disease, injury including wound healing, bone disease, tooth disease, osteoarthritis, periodontal disease, cerebrovascular ischemia, renal failure and brain injury.
GDF-5 (also known as cartilage derived morphogenetic factor) may be used in the treatment of arthritis, arthropathy, and neoplasm.
BMP10 may be used to treat osteoporosis, wound healing, ulcer, periodontal disease, bone disease, burns, connective tissue disease, bone tumour, bone injury and neoplasm.
BMP-8 (also known as osteogenic protein 2) may be used in the treatment of bone disease.
BMP-6 has therapeutic applications in the treatment of cerebrovascular ischemia and cancer.
BMP-7 may be used in the treatment of renal disease, calcification, tooth disease, motor neurone disease, Parkinson's disease, periodontal disease, bone diseases, cerebrovascular ischemia, renal failure, brain injury, scar tissue, musculoskeletal disease, and osteoporosis.
BMP-2 may be used for treating osteoporosis, bone diseases including musculoskeletal diseases and periodontal disease.
BMP-4 may be used in the treatment of kidney diseases.
GDF-3 has therapeutic uses in the treatment of immune disorders, whereas GDF-1 may be used in the treatment of nervous system injuries, multiple sclerosis and neurological diseases.
GDF-8 (also known as myostatin) may be used in the prevention and/or treatment of muscle wasting disease and non-insulin dependent diabetes.
The inhibin family of proteins may be used to treat infertility, haematological disease, anaemia, carcinoma, leukaemia and hyperphosphatemia and cancers, as well as in contraception.
Activin has therapeutic uses in the fields of scleroderma, angiogenesis disorders, scarring and fibrosis, restenosis, adhesions, endometriosis, ischemic disease, bone and cartilage induction, in vitro fertilisation, oral mucositis and wound healing.
GDF-15 may be used to treat Parkinson's disease, Alzheimer's disease, schizophrenia, cerebrovascular ischemia, dementia, immune disorders and neoplasm.
Mullerian inhibitory factor (MIF), which is also known as anti-Mullerian hormone or MIS, may be used in the fields of cancer including metastasis, lymphoid leukaemia, prostate tumour, uterine cervix tumour, breast tumour, ocular tumour, ovary tumour endocrine disease, haemangioma, endometriosis, inflammation, melanoma, neoplasm, carcinoma, skin tumour, female genital tract tumour, male genital system disease, erectile dysfunction and respiratory distress syndrome.
Ebaf (also known as Lefty) may be used in the treatment of hair disease including alopecia, scleroderma, fibrosis, muscular dystrophy, neoplasm, autoimmune disease, treatment of scar tissue, cirrhosis, pulmonary fibrosis, melanoma and carcinoma.
Despite the well-recognised requirement for pharmaceutical compositions comprising TGF-β superfamily members there are many acknowledged problems associated with presently existing compositions. Among these problems are the common inability to recover a proportion of a TGF-β superfamily member incorporated in a given composition (a problem which may arise as a result of adsorption of the TGF-β superfamily member to the material of a container in which the composition is stored), and a generally observed decrease over time of the biological activity of TGF-β superfamily members incorporated and stored in compositions. This also has important implications in the manufacture of any TGF-β superfamily member therapeutic.